IGF AXIS IN PULMONARY VASCULAR REMODELING

IGF 轴在肺血管重塑中的作用

• 批准号: 2702071
• 负责人: SUSAN F TOWNSEND
• 金额: $ 8.4万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2702071
• 关键词: antisense nucleic acid; cow; disease /disorder model; embryo /fetus; exoribonucleases; fibroblasts; gene expression; growth /development; hemodynamics; immunocytochemistry; in situ hybridization; newborn animals; perinatal; polymerase chain reaction; pulmonary circulation; pulmonary hypertension; respiratory hypoxia; tissue /cell culture; vascular endothelium; western blottings

The role of IGF-II and IGF-BP's in the dramatic pulmonary vascular remodeling associated with neonatal pulmonary hypertension will be studied. The fibroproliferative response in this disease characterizes the neonate, and may represent a unique developmental susceptibility to injury at a time of marked changes in circulatory physiology and vessel maturation. Our preliminary data suggest a role for increased expression of IGF-II in the vascular proliferative response. IGF-BPs produced by vascular wall cells play a central role in localizing and modulating IGF actions at the cellular level. We hypothesize that increased IGF-II expression in the pulmonary vessel wall is a critical modulator of the vascular proliferative response in neonatal hypoxic pulmonary hypertension. We propose that increased IGF-II expression in neonatal pulmonary hypertension reflects persistence of a fetal pattern of gene expression in the perinatal period, associated with altered expression and accumulation of specific IGF-BP's. We postulate that altered expression of IGF-II and IGF-BP's is regulated by hypoxia in vitro, with different effects on the adventitial fibroblast and vascular smooth cell. The goals are: 1) to evaluate the normal developmental changes in IGF-II and IGF-BP expression in the pulmonary circulation during late fetal and early neonatal life, and how these are affected by developing hypoxic pulmonary hypertension in the newborn, and 2) to examine directly how hypoxia alters expression of IGF-II and IGF-BPs in fetal, neonatal, and hypertensive vascular wall cells in vitro.

IGF-II 和 IGF-BP 在肺血管显着变化中的作用 与新生儿肺动脉高压相关的重塑 研究过。 这种疾病的纤维增殖反应的特点是 新生儿，可能代表了一种独特的发育易感性 循环生理和血管发生显着变化时受伤 成熟。 我们的初步数据表明增加表达的作用 IGF-II 在血管增殖反应中的作用 IGF-BPs 产生于 血管壁细胞在定位和调节 IGF 中发挥核心作用 细胞水平的行动。 我们假设 IGF-II 增加 肺血管壁中的表达是关键的调节因子 新生儿肺缺氧的血管增殖反应 高血压。 我们建议新生儿中 IGF-II 表达增加 肺动脉高压反映了胎儿基因模式的持续存在 围产期表达，与表达改变相关 和特定 IGF-BP 的积累。 我们假设改变了 IGF-II 和 IGF-BP 的表达在体外受缺氧调节， 对外膜成纤维细胞和血管平滑细胞有不同的作用。 目标是：1) 评估 IGF-II 的正常发育变化 胎儿晚期和晚期肺循环中 IGF-BP 的表达 新生儿早期生活，以及缺氧如何影响这些生活 新生儿肺动脉高压，2) 直接检查 缺氧会改变胎儿、新生儿和新生儿中 IGF-II 和 IGF-BP 的表达 体外高血压血管壁细胞。